With the great progress of civilization, cancer morbidity has been reported to increase. Despite the increasing incidence of cancer, therapies for cancer still fall within the scope of surgical operation, radiotherapy, and chemical therapies using about 40 chemicals having strong cytotoxicity. However, these therapies are useful only in cancer patients in early stages, or are effective only for certain types of cancer. Despite these therapies, cancer mortality is currently tending to increase.
Death from cancer is mainly due to the metastasis of cancer cells into other tissues rather than due to initial tumors. Active research on the infiltrative and metastatic mechanism of cancer cells and the prevention thereof has been conducted in an effort to reduce cancer mortality.
To metastasize, a cancer cell must break away from the primary tumor, invade support structures of normal tissue, such as interstitial space or capillary basement membranes, to attach to either the circulatory or lymph system, degrade extracellular matrixes and basement membranes, circulate through the bloodstream, and grow at distant loci (metastasize) as a secondary tumor in normal tissues elsewhere in the body, with the concurrent generation of blood vessels (angiogenesis).
Accordingly, the process of metastasis is mainly comprised of attachment, invasion and angiogenesis. If any of them is prevented from happening, cancer metastasis can be prevented. In the invasion of cancer cells, matrix metalloproteinases (MMPs), secreted from the attached cells, are known to play important roles.
MMPs are enzymes involved in the degradation of the extracellular matrix (ECM), such as collagen, proteoglycans, etc, and are represented by, for example, interstitial collagenase, MMP-2, and stromelysin. Also, MMPs, a family of zinc-dependent endopeptidases, must undergo zymogen activation by other proteases or organic phosphorus compounds prior to expressing any proteolytic activity. Their activity is inhibited by TIMP (tissue inhibitor of metalloproteinase) that is secreted together with MMPs. Sharing high cDNA sequence homology, MMPs are collectively classified as a family. MMPs are found to be involved in many pathological conditions, including abnormal connective tissues and basement membrane matrix metabolism, such as tissue ulceration, abnormal wound healing, periodontal disease, bone disease, tumor metastasis or invasion as well as HIV infection (J. Leuk. Biol., 52 (2): 244-248, 1992). In fact, cancer cells, which actively metastasize, show high activity of MMP2 or MMP9, compared to normal cells or non-metastatic cancer cells, and inhibitors of the MMPs are shown to prevent cancer metastasis.
With this background, the present inventors succeeded in isolating and purifying obovatol and obovatal from Magnoliaceae (Magnolia obovata Thunberg), which has been used as a herbal medicine, and found that such compounds have the activity of inhibiting the expression and enzymatic activity of MMPs, which play pivotal roles in the growth and metastasis of various human cancer cells.